Medical | Nicole Jensen, MD| June 30, 2020
Developing a safe and effective SARS-CoV-2 vaccine during the COVID-19 pandemic is a complex process. Here are the steps required to create a vaccine.
Vaccine development is commonly a long, arduous process. In the middle of the COVID-19 pandemic, however, the world needs a SARS-CoV-2 vaccine now.
The first step in vaccine design is identifying the vaccine target, or “antigen of interest” from the pathogen. The surface of SARS-CoV-2 is surrounded by spike proteins which allow it to enter human cells via interaction with the ACE2 receptor. Fortunately, we know from past research on SARS-CoV-1 and MERS-CoV that the spike protein on SARS-CoV-2 is likely an ideal vaccine target. In order to generate immunity for SARS-CoV-2, a vaccine should induce a robust and well-rounded immune response to the spike protein including T cells and neutralizing (not just binding) antibodies that will subsequently prevent SARS-CoV-2 from infecting human cells.
There are multiple platforms for delivery of the spike protein to host immune cells (i.e. antigen presenting cells) that initiate immunity to SARS-CoV-2. Whole pathogen vaccines, (attenuated or inactivated) subunit vaccines, nucleic acid vaccines and viral vector vaccines are all possible options for a SARS-CoV-2 vaccine, each with their own unique advantages and disadvantages.
Once a candidate vaccine is engineered, it must go through several trials before it is approved for public use. Candidate vaccines are initially tested on animals in preclinical trials and involve evaluating safety, immunogenicity and efficacy. Following preclinical trials, a candidate vaccine may receive approval for human testing, starting with phase I trials. Phase I trials evaluate safety, reactogenicity (typical vaccine side effects like injection-site pain, redness, fever) immunogenicity, schedule and dosing in a small group of healthy participants. Phase II trials are scaled-up version of phase I trials and include some of the target population. Vaccine efficacy is finally evaluated during phase III trials. If a new vaccine receives FDA approval, it moves on to Phase IV trials which assess long term safety and effectiveness.
Typically, each of these steps can take months, if not years and follow each other sequentially. On average, preclinical and clinical trials together take 15-20 years. Fortunately, and for multiple reasons, when it comes to SARS-CoV-2 this timeline has been significantly accelerated. Here’s why — first, we have a lot of data from SARS-COV-1 and MERS-CoV to work from. We also have the whole world working towards the same goal; according to the World Health Organization (WHO) as of the end of June, there are 141 vaccine candidates with 16 already in clinical trials. Preclinical and clinical trials have also started to overlap which is compressing the timeline. There are also lots of willing volunteers and fast-tracked federal approvals which make estimates for a vaccine by mid-2021 (instead of 2035 under normal circumstances) more attainable.
Despite such fervor in development, there are significant challenges and potential risks going forward. Ironically, it may be difficult to show that a candidate vaccine is effective in phase III trials if social distancing or other mechanisms to decrease spread (masks, hand washing) slow the rate of new infections. One way to get around this is to choose participants for phase III trials that are already at an increased risk of getting infected with SARS-COV-2, such has healthcare workers, persons living in congregate settings or essential workers in close contact settings like factories. Another more ethically questionable option is to conduct Human Challenge Trials in which participants are inoculated with the candidate vaccine and then deliberately exposed to SARS-CoV-2.
Human Challenge Trials aside, there is also a potential risk for antibody dependent enhancement as a result of the candidate vaccine. This is a phenomenon in which binding of virus to non-neutralizing or binding antibodies can enhance viral entry into cells and lead to increased infectivity and virulence. This is one reason why maintaining the integrity of the spike protein when creating a vaccine candidate for SARS-CoV-2 is so important — because an alteration in the spike protein could ultimately lead to binding instead of neutralizing antibodies.
Typically manufacturing begins after clinical trials have concluded. Several groups like the Coalition for Epidemic Preparedness Innovations (CEPI) and the Advanced Research and Development Authority (BARDA) however, are making upfront investments in manufacturing in anticipation of a vaccine for SARS-COV-2. And ultimately investment will drive distribution. To counter this, the WHO launched a global initiative to ensure equitable access to a vaccine worldwide and groups (like CEPI) and countries all over the world have pledged their support.
Realistically, to meet global demand, we are going to need more than one vaccine. Having more than one vaccine available will help avoid bottlenecks in manufacturing and some vaccines may be more effective in certain populations. Despite the obstacles, given the progress made in just six months from the first documented cases of SARS-CoV-2, there is certainly room for hope for a safe and effective SARS-CoV-2 vaccine in the future.
Nicole Jensen, MD, completed medical school at State University of New York (SUNY) Downstate College of Medicine and is a recent graduate of the University of Virginia (UVA) Family Medicine Residency Program. She will be staying at UVA as a Faculty Development Fellow next year.
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